The present invention relates to new diphenylurea compounds.
The invention relates also to their use as mixed xcex12/5-HT2c ligands.
Compounds having a diphenylurea structure have been described in the Application JP 11130750 for their serotonergic antagonistic properties, and in the Application WO 99 32436 for their use as raf kinase inhibitors.
The frontal cortex plays an essential role in the processes that control the functions affected in psychiatric disorders. In particular, it is now accepted that the disturbance of monoaminergic transmission is strongly implicated in the etiology of those various disorders. For example, in the case of depression, monoaminergic activity is reduced in the corticolimbic regions.
Among the various monoamine auto- and hetero-receptors implicated in regulatory mechanisms, xcex12-A.R. (autoreceptors) and 5-HT2c receptors have proved to be of major importance. Those two receptor sub-types act in the same way by inhibiting dopaminergic and adrenergic transmission. On the one hand a retrocontrol is exerted by xcex12-A.R. receptors on noradrenergic neurons (J. Pharmacol. Exp. Ther., 1994, 270, 958), and on the other hand 5-HT2c receptors exert an inhibiting control on dopaminergic and noradrenergic transmission (Neuropharmacology, 1997, 36, 609).
In the past, compounds binding one or the other of those receptor sub-types have demonstrated their potential in the treatment of a plurality of pathologies.
For example, the beneficial role of xcex12 antagonist compounds has been studied in the treatment of cognitive disorders (J. Pharmacol., 1992, 6, 376), Parkinson""s disease (CNS Drugs, 1998, 10, 189), libido disorders and sexual dysfunction (J. Pharmacol., 1997, 11, 72). Similarly, 5HT2c receptor antagonist compounds have demonstrated their usefulness in the treatment of sexual dysfunction (ref. J. Pharmacol., ibid.), Parkinson""s disease (Drug News Perspect., 1999, 12, 477), and also anxiety (Br. J. Pharmacol., 1996, 117, 427) and schizophrenia (Neurosci. Lett., 1996, 181, 65).
Compounds having a dual xcex12-A.R. and 5-HT2c antagonist character may be of significant use for clinicians for achieving, with the administration of a single compound, an appreciably enhanced action in the restoration of neurotransmission by means of a synergistic effect. That kind of compound furthermore presents a considerable advantage in comparison with the administration of two different products.
The compounds of the invention have a novel structure that confers on them such a dual xcex12/5-HT2c antagonist character, and they are accordingly useful in the treatment of depression, anxiety, schizophrenia, Parkinson""s disease, cognitive disorders, libido disorders and sexual dysfunction, sleep disorders, drug abuse, and impulsive behaviour disorders.